delta-pregnenes



United States Patent M-PREGNENES Seymour Bernstein, Pearl River, N. Y., and Robert Herman Lenhard, Ridgefield Park, N. 1., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application June st), 1955,

Serial No. 519,249

6 Claims. c1. 260-397.45)

This invention relates to new steroid compounds. More particularly, it relates to 9a-halo-l6 a-hydroxy-hydrocortisone, esters thereof and methods of preparing the same.

It has been known that 9a-fluoro-hydrocortisone is more active than hydrocortisone; Fried et al.; J. Am.

1 Chem. Soc. 75 2273 (1953), and 76 1455 (1954). However, 9ot-fluoro-hydrocortisone has such a high electrolyte activity; (sodium retention) that it can be used only topi 2,773,080 Patented Dec. 4,: 195 6 d 2. tained at from about 10 C. to C; Following completion of the reaction, which can range from 30 minutes to several hours, the reaction mixture is usually poured into ice water and neutralized with mild alkali. The desired product is then extracted with a solvent, .for example chloroform. On evaporation of the solvent, the crude product isobtainedwhich canbe purified by con ventional methods. Following completion of the reaction, the reaction mixture can be evaporated to dryness directly and product purified byrecrystallization or .othe'r wellknown methods. 7 V I 7 The Sa-fluoro-16a-hydroxy-hydrocortisone of the present invention is very active physiologically Its activity reaches, and in many instances exceeds, that of cortisone or hydrocortisone without the undesirable side effects of i the latter. It can be used both internally for systemic cifect'andtopically' for local efiect, e. g.', in such condihydrocortisone. In the thymus involution test described by R. I. Dorfman, Physiological Reviews, 34, 158 ("1954), the present compounds show activity comparable to 9mfl'uoro-hydrocortisone acetate without the undesirable electrolyte activity (sodium retention). At higher dosage levels the present compounds act as sodium excretors which areuseful' in thetreatrnent of edemas. The new compounds [in the cotton ball test described by Meier et al., Experientia 6, 469 (1950)] also show anti-inflam- "matory action which is atleast equal to that of cortisone acetate.

The compounds of thepresent invention can be illustrated by'the following general formula:

The compounds of the present invention are relatively tions as. rheumatoid arthritis and atopic dermatitisfjlhe compound can be used, therefore, in the form of capsules, pills, tablets, solutions for injection, ointments, salves, and the like. i

The following examples describe in detail thepreparation of 9a-halo-16a-hydroxy-hydrocortisone and deriva-v tives thereof. i

Example 1 A solution of 0.70 g. of A '-pregnatriene-2l-ol 3,20-dione. Zl-acetate and 0.50 g. of osmium tetroxide in 10 ml. of benzene and 0.5 ml; of pyridine was allowed to standat room temperature for 18 hours. The osmate ester was decomposed by the addition of 35 ml. of water, 10 ml. of benzene, 23 ml. of methanol and 3.58 'g. each of sodium sulfite andpotassium bicarbonate. After stir ring the mixture for 5 hours, approximately 150 ml. of chloroform was added and the stirring continued for /2 hour. The mixture'was filtered'through diatomaceous earth, the residue washed with hot'chl'oroform and the ,organic layer separated. The aqueous phase was extracted several times with chloroform and the combined extracts were washed with saturated saline and with water. The dried extract was evaporated under' reduced 1 pressure and the residue crystallized from acetone-petro- J tate, melting 'point 195-1915- with previous softening.

was added 2 ml. of acetieanhydride, and the mixture was allowed to stand. at room temperature for 3 days. The;

solution was poured into water, l .cooled and"thc product was filtered and washedwith .water to give 0.33, g." of

pure. A -pregnadiene m ma triol- 3,20 5 dione' 16u, 2l -diacetate, melting point 193-195 with previous softening.- Two. crystallizatious from acetone-petroleum highrnelting crystalline solids TheyareQsoluble inthe common organic solvents and relatively insoluble in water;

The compounds are preparedfrom Af -pregnenes suchxQfiJIfl-OxideWhich are described and claimed in our cohalogenohydrins, the compounds of the present invention.

The reaction-is genral'l-y'.-carlried but" lira. solvent such as chloroform, carbon tetrachlorideand the like-.j 'The tem-.

perature range during the course of the reaction is maine ether'gave 0.28v g. of pure diacetate, melting point 194-- I 12-5",with previous softening; Mm}. abs. 2110. 238- 239 mu earth. andevaporated under reduced. pressure to an oil... Crystallizationfrom acetone petroleum ether gave 0.45 g;

1 325 mgg of dhm -pre gnadiene-l6a,: ..'17u,2l-triol-3,20-dione ZI-acetate' in; 20 ml. of pyridinc Example 2 A solution of 14.5 g. of A -pregnene-9a-bromo-l1,8, 16a,17a,21-tetrol-3,20-dione 16a,21-diacetate and 3.2 g. of anhydrous potassium acetate in 1 l. of absolute alcohol wasrefluxed for 18.5 hours. evaporated to dryness and the residue dissolved in ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined extracts were washed with saturated sodiumbicarbonate solution and saline.

The dried extract was evaporated and the residue was dissolved in 35 ml. of pyridine, treated with 10 ml. of acetic anhydride and allowed to stand at room temperature overnight. Methanol and benzene were added and the solution was evaporated to dryness. Crystallization of the residue from methanol gave 6.5 g. :of crude oxide diacetate, melting point 171.5-191L5" with previous softening, suitable for use in further transformations.

A solution of 360 .mg. of the oxide diacetate, A -pregnene 16a,17a,21-triol 3,20 dione 9 6,115 oxide 16a,21-diacetate in 25 ml. of chloroform (alcohol free) was treated with approximately 1 ml. of anhydrous hydrogen fluoride and allowed to stand at about -10 for 2 hours. The reaction mixture was then poured into ice water, neutralized with saturated sodium bicarbonate solution and extracted several times with chloroform. The washed and dried extract was evaporated to dryness and the residue was dissolved in 5 ml. of pyridine, treated with 2.5 ml. of acetic anhydride and allowed to stand at room. temperature overnight. Methanol and benzene were added, and the solution was evaporated. to dryness. The. residue was crystallized from acetone-petroleum ether to give 146mg. of crude fluorohydrin. Recrystallization fromacetone-petroleum ether gave 123 mg, melting point 231.5-235.5' (Kofler hot stage). A 62 mg. portion of the latter was recrystallized from acetonepetroleum ether to give 59 mg. of A -pregnene- 9a-fluoro- 1 15,16a,17a,21-tetrol-3,20 dione l6oc,21-dlaC6tal, melting point 230.5-234.5 (Kofler hot stage), 231.5237 .5 (capillary). The long colorless needles as obtained were solvated. .The analytical sample when dried for 16 hours over refluxing xylene melted at237239 with previous softening (capillary), and there was a 10% loss in weight;

. T Example 3. :J

The reaction mixture was form saturated with hydrogen chloride. After allowing to stand at 0 for 4.5 hours, the solution was evaporated to dryness. The resultant solid, after treating with activated charcoal, was crystallized from acetone-petroleum ether to give 99 mg. of the chlorohydrin, melting point 211.52l3.5. Three crystallizations from acetonepetroleum ether gave 80 mg. of pure A -pregnene-9uchloro 1lfi,16a,17a,21 tetrol 3,20 dione 160:,21- diacetate, melting point 214.5215.5 (dependent upon the rate of heating and when inserted in the bath; Amax. abs. alc. 240.5 m (15,800); [a] -l-76 (chloroform).

Example 5 A solution of 144 mg. of the chlorohydrin, A -pregnene 9a chloro 11fi,16a,17ot,21 tetrol 3,20 dione l6a,21diacetate in 10 ml. of dry methanol was treated with 5 ml. of methanol containing 14 mg. of sodium. Dry nitrogen was bubbled through both solutions for 5 minutes before the addition of the sodium methoxide. The reaction was allowed to proceed at room temperature for 10 minutes, and then neutralized with 0.05 ml. of glacial acetic acid. By concentrating the reaction mixture to about 10 ml., 46 mg. of crystalline material which did not melt at 300 was obtained. The addition of water to the mother liquor afforded a small amount of solid. Since the recovery was poor, both solid and mother liquor were combined and after adding saturated saline solution to the mixture, extraction was attempted with ethyl. acetate, ether, benzene, chloroform and methylene chloride. All of the solvents :tried proved unsuitable. The organic extracts were separated and the aqueous phase was filtered'to afford 50 mg. of solid which was added to the combined extracts. After evaporation, the residue was dissolved in a large amount of boiling acetone (a small amount of material which was also insoluble in water was removed by filtration). Concentration of the acetone gave 37 mg. of A -pregnene- 9a-chloro l1fl,16 z,l7oc,2l tetrol 3,20 dione; material darkens but does not melt at 360, positive Beilstein and Blue Tetrazolium tests. Crystallization from methanol gave 24mg. of product, begins to darken at 190 but Dry nitrogen was bubbled for.15 minutes through a 7 solution of "150 mg. of A pregnene- 9oz-fluoro-11 8,160,- -172l-tetrol-3,20,-dione ,1'6a ,21-diacetate and throughlO mlf'of methanol containing 14 mg. of sodium. The sodium methoxi'de solutionf was then introduced to. the

steroid solution and allowed to remain atroom tempera A ture-for'lO minutes under nitrogen. After theaddition of 0.05 ml. of glacial acetic acidgthe reaction mixture was evaporated to dryness under reduced pressure.

Water;was added-to the residue and thecrude product was filtered and washed with water to afford .85 mg,

melting point 238-244", with previous". softening and browning. Two crystallizati-ons from acetone-petroleum ether' gave mg. of the pure A -pregnene-9d fiuoro 11316a,17u,2l-tetrol-3,20-dione, melting point 257-260; with decomposition and previous" softening and browning;

Example 4 of chloroform (alcohol free) was'added 10 of chlorodoes not melt at 400 (due to the unusually high melting point, further recrystallization was not attempted; Mnax. abs. alc. 240240.5 m (615,900).

---orr V in which R and R are members of the group consisting of hydrogen and loweralkanoyl radicals and Hal is a halogen radical. a

2. The compound A -pregnene-9a-fiuoro-1lB,16a,17a,-

" 2l-tetrol-3,20-dione. a

-3.' The compound A -pregnene-9a-chloro 11,8,16a,l7a,- 21-tetrol-3,20-dione.

' 4. The compound A -pregnene-9u-fluoro-11fi-16a,17m,- 2l-tetrol-3 ,20-dione- 16a',21 diacetate.

21-tetrol-3,20 dione16a,21 diacetate.

' To a' solution; of 100 mg. of A -pregnene 1 6a,17u,21- triol-3,20-dione-9 8,1lB-oxide 16,2l-diacetate in '2 ml.

' 6. The compound A -pregnene9 t-bromo-l1,6,16a,17a,- 2l-tetrol-3,20 dione 16 a,2l-diacetate.

I References Cited inthe file of this patent UNITED STATES PATENTS 2,707,190 Farrar Apr. 26, 1955 

1. A COMPOUND SELECTED FROM THOSE HAVING THE GENERAL FORMULA: 